Tyro3介导肿瘤细胞与微环境浸润中性粒细胞串话促进宫颈癌放疗抵抗的机制研究

放疗抵抗是影响宫颈癌远期疗效的主要因素之一，机制仍不清楚。前期通过810例泛癌组织芯片筛选发现受体酪氨酸激酶Tyro3主要高表达于宫颈癌，并在根治性放疗患者中表达越高、预后越差；宫颈癌小鼠模型中Tyro3高表达增加放疗抵抗性；Tyro3表达与微环境中性粒细胞（TAN）浸润正相关。机制初探提示Tyro3可能促进肿瘤释放CCL3趋化微环境TAN、TAN反馈激活肿瘤MAPK通路诱导宫颈癌放疗抵抗。据此提出“高表达Tyro3可通过释放CCL3介导肿瘤细胞与微环境TAN之间正反馈串话，进而诱导宫颈癌放疗抵抗”的科学假说。项目拟通过体内外实验明确Tyro3诱导宫颈癌放疗抵抗的功能，采用共培养体系及小鼠模型、设计拯救实验阐明Tyro3与TAN串话介导放疗抵抗的机制，最后临床大样本验证Tyro3/TAN/MAPK反馈环与宫颈癌放疗抵抗的相关性。本研究的成功实施，将为逆转宫颈癌放疗抵抗提供新理论和新靶点。

Radioresistance is one of the main factors affecting the long-term curative effect of cervical cancer, and the mechanism is still unclear. Previously through 810 cases of pan-cancer tissue array screening, we found that the receptor tyrosine kinase Tyro3 was mainly expressed in cervical cancer, and the higher the expression in patients receiving radical radiotherapy, the worse the prognosis. High expression of Tyro3 in cervical cancer mice model increased the resistance to radiotherapy. Moreover, Tyro3 expression was positively related to the infiltration of tumor-associated neutrophils (TAN). Preliminary exploration of mechanism suggested that Tyro3 might promote the release of CCL3 that led to the chemotaxis of TAN, which in turn activated MAPK signaling pathway in tumor cells to induce radioresistance of cervical cancer. Therefore, we speculated that "high expression of Tyro3 could induce a positive feedback crosstalk between tumor cells and TAN, thus inducing radioresistance of cervical cancer". We intend to clarify the function of Tyro3 in inducing radioresistance through in vitro and in vivo experiments, and explain the mechanism of the crosstalk between Tyro3 and TAN in mediating radioresistance using co-culture system, mouse model and rescue experiments. Finally, we intend to verify the correlation between Tyro3/TAN/MAPK feedback loop and radioresistance of cervical cancer through large clinical samples. The successful implementation of this study will provide a new theory and a new target for reversing the radioresistance of cervical cancer.